It is known that asthma is a disease characterized by a reversible airway obstruction which is accompanied by chronic inflammation and overreaction of airway and that CD4+ T cells, particularly Th2 cell is taking an important role. It is known that Th2 cell is differentiated from Thp cell by IL-4, and that IL-4 and IL-13 produced from Th2 cell cause airway contraction and chronic inflammation of airway through inducing production of IgE antibody production, activation and infiltration of eosinophil and increase of mucus secretion. In addition, it has been reported that IL-13 is also participated in the airway epithelial hypertrophy and airway sub-epithelial fibrosis (J. Clin. Invest., 103, 6, 779-788, 1999), destruction of alveolus (J. Clin. Invest., 106, 1081-1093, 2000) and the like symptoms which are found in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and the like.
STAT 6 (signal transducer and activator of transcription 6) is participated in the intracellular signal transduction of IL-4 and IL-13. It has been reported that differentiation of Th2 cell from Thp cell does not occur by the deletion of STAT 6 (Immunity, 4, 313-319, 1996) and that production of IgE, acceleration of airway reactivity and infiltration of eosinophil into airway and lung are inhibited in an asthma model of STAT 6 deletion mouse (J. Exp. Med., 187, 9, 1537-1542, 1998). These reports suggest that STAT 6 participates in inflammatory respiratory diseases such as asthma and the like.
Also, It has been reported that STAT 6 and IL-4 mRNA in nasal mucosa increase by administration of antigens to patients of allergic rhinitis (Clin. Exp. Allergy, 30, 86-93, 1709-1716, 2000) and also that dermatitis-like symptoms such as infiltration of inflammatory cells into the skin are induced by effecting over-expression of IL-4 in mice (J. Tnvest. Dermatol., 117, 4, 977-983 (2001)). These reports suggest that STAT 6 participates in allergic rhinitis and dermatitis.
STAT 6 is bonded to GYKXF motif of IL-4 receptor a chain (IL-4Rα) which is a constituting factor of IL-4 receptor and IL-13 receptor (Science, 165, 1265-1267, 1994), and a JAK family kinase is also bonded to these receptors. When IL-4 or IL-13 is bonded to a receptor, STAT 6 is dimerized by undergoing tyrosine-phosphorylation by the JAK family kinase and translocated into the nucleus where it exerts a function as the transcription factor (Science, 165, 1265-1267, 1994). Accordingly, if any one of these steps, for example, the tyrosine-phosphorylation of STAT 6, can be inhibited, it becomes possible to inhibit the function of STAT 6 as a transcription factor so that its effectiveness is expected in treating the aforementioned various diseases in which IL-4 and IL-13 are participated.
Since Syk tyrosine kinase as a Zap/Syk family kinase classified into a genealogical relation different from the JAK family kinase based on the gene sequence genealogical tree (Genome Biology, 3, research 0043.1-0043.12) mediates signals from antibody receptors (FcεRI, EcγR) and antigen receptors (BCR, TCR) and apoptosis inhibition signal of eosinophil by GM-CSF, it has been reported that an Syk inhibitor is expected as an agent for inflammations including asthma or allergic diseases (e.g., Patent Reference 1). However, there are no reports on the participation of Syk in the signals of IL-4 and IL-13. It is considered that an Syk inhibitor expresses its effect by inhibiting all of the activation via respective antigen receptors of B cell and T cell, inhibiting antibody production in the case of antibodies regardless of their subclasses and inhibiting differentiation of helper T cell nonspecifically. That is, it is predicted that Syk inhibitors always accompany inhibitory action of infection protection, immunological functions and the like. In the case of STAT 6 inhibitors on the other hand, since the function of STAT 6 is specific for IL-4 and IL-13, they specifically inhibit production of IgE in the case of antibodies and differentiation of Th2 in the case of T cell subsets. Accordingly, it is expected that STAT 6 inhibitors are effective as agents for treating allergic or inflammatory respiratory diseases having less influences upon infection protection, immunological function and the like (J. Clin. Inves., 109, 1279-1283, 2002).
Diaminopyrimidine-5-carboxamide derivatives-useful for the treatment of inflammatory and allergic diseases, immune diseases and the like based on the Syk tyrosine kinase inhibition have been reported and, for example, the following compound has been reported in Patent Reference 1.
(Z represents O, NR2 or a bond and A represents a lower alkyl, aryl or the like which may have a substituent(s), wherein —NH2, —NH-lower alkyl, —N(lower alkyl)2, —NH-lower alkylene-aryl, —NH-cycloalkyl, —NH-aryl, —NH-heteroaryl and the like are disclosed as substituents of said aryl which may have a substituent(s), but they are not a saturated hetero ring, and there is no illustrative disclosure of the 3-chloro-4-hydroxyphenyl group as a substituent of the lower alkyl which may have a substituent. See said published application for details.)
However, there is no disclosure not only on the action of said compound upon STAT 6 but also on its action upon IL-4 and IL-13. Also, since Syk tyrosine kinase concerns itself in the signal transduction of B cell, T cell, mast cell or the like when these cells are stimulated with an antigen, the effect of its inhibitor as an agent for treating inflammatory diseases can be expected, but its immunosuppressive effects and the like must also be taken into consideration.
In addition, compounds having antiviral activities, including diaminopyrimidine-5-carboxamide derivatives, represented by the following general formula have also been reported (e.g., Patent Reference 2).
(X represents —NR3R4 or the like, Y represents —N(R6)— or the like, R1 represents —C(O)NR7R8 or the like and R5 represents aryl or the like, and said aryl may be substituted with —NR′R″, —R′ or the like, wherein said R′ and R″ represent hydrogen, (C1-C8)alkyl, aryl, aryl-(C1-C4)alkyl or aryloxy-(C1-C4)alkyl, but they are not a saturated hetero ring, and there is no disclosure on the illustrative compounds in which the R5—Y moiety is 4-hydroxyphenetyl group. See said published application for details.)
Also, other pyrimidine-5-carboxamide derivatives useful as PDE 5 inhibitors (e.g., Patent Reference 3; the 2-position substituent of the pyrimidine ring is a lower alkylamino or indanylamino group which may be substituted), NOS inhibitors (e.g., Patent Reference 4; imidazolylphenyl group and 1,3-benzodioxol-5-yl group are essential), anticancer agents (e.g., Patent Reference 5; the 4-position substituent of the pyrimidine ring is an amino group which is directly bonded to a ring group), anti-fugal agents (e.g., Patent Reference 6; an alkynyl group is essential on the 4-position substituent of the pyrimidine ring) and the like have been reported, but all of them do not disclose or suggest on the inhibitory activity for STAT 6 activation.
In addition, dihydrothiadiazole derivatives (e.g., Patent Reference 7), imidazopyrimidine derivatives (e.g., Patent Reference 8), benzofuran derivatives (e.g., Patent Reference 9), imidazo[2,1-b]thiazole derivatives (e.g., Patent Reference 10), tetrahydroquinoline derivatives (e.g., Patent Reference 11) and the like have been reported as STAT 6 activation inhibitors, but there are no reports on pyrimidine derivatives.
Patent Reference 1                International Publication No. 99/31073 pamphlet        
Patent Reference 2                International Publication No. 99/41253 pamphlet        
Patent Reference 3                International Publication No. 01/83460 pamphlet        
Patent Reference 4                International Publication No. 01/72744 pamphlet        
Patent Reference 5                International Publication No. 00/39101 pamphlet        
Patent Reference 6                German Patent Application Publication. No. 4029650 specification        
Patent Reference 7                JP-A-2000-229959        
Patent Reference 8                International Publication No. 02/14321 pamphlet        
Patent Reference 9                International Publication No. 02/53550 pamphlet        
Patent Reference 10                JP-A-11-106340        
Patent Reference 11                International Publication No. 02/79165 pamphlet        
Since inhibitors of STAT 6 activation are expected as agents for treating respiratory diseases such as asthma, COPD and the like, great demand has been directed toward the development of novel compounds.